The beneficial substances comprise broccoli-derived sulforaphane and quercetin, which is found in high-levels in onions.

The team used these insights to develop new food supplements, which are currently being trialled to decrease risk of developing diabetes and heart disease.

Published by Antioxidants and Redox Signalling, the research investigated the ways in which compounds in fruit and vegetables keep humans healthy.

Oxidative stress in health and disease: The therapeutic potential of Nrf2 activation
For the past 40 years or so, oxidative stress has been increasingly recognized as a contributing factor in aging and in various forms of pathophysiology generally associated with aging. Our view of oxidative stress has been largely “superoxide-centric”, as we focused on the pathological sources of this oxygen-derived free radical and the types of molecular havoc it can wreak, as well as on the protection provided by the antioxidant enzymes, especially the superoxide dismutases, catalases, and glutathione peroxidases. In the last decade our view of oxidative stress has broadened considerably, and it is now often seen as an imbalance that has its origins in our genes, and the ways in which gene expression is regulated. At the center of this new focus is the transcription factor called nuclear factor (erythroid-derived 2)-like 2, or Nrf2. Nrf2 is referred to as the “master regulator” of the antioxidant response, modulating the expression of hundreds of genes, including not only the familiar antioxidant enzymes, but large numbers of genes that control seemingly disparate processes such as immune and inflammatory responses, tissue remodeling and fibrosis, carcinogenesis and metastasis, and even cognitive dysfunction and addictive behavior. Thus, the dysregulation of Nrf2-regulated genes provides a logical explanation for the connections, both direct and indirect, between observable oxidative stress and perhaps 200 human diseases involving these various physiological processes, each reflecting a network involving many gene products. The evolutionary self-association of these many genes under the common control of Nrf2 suggests that the immune and inflammatory systems may present the largest demand for increased antioxidant protection, apart from constitutive oxidative stress resulting from mitochondrial oxygen consumption for metabolic purposes. Gene expression microarray data on human primary vascular endothelial cells and on the SK-N-MC human neuroblastoma-derived cell line have been obtained in response to the dietary supplement Protandim, a potent composition of highly synergistic phytochemical Nrf2 activators. Pathway analysis of results shows significant modulation by Protandim of pathways involving not only antioxidant enzymes, but of those related to colon cancer, cardiovascular disease, and Alzheimer disease.

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Brooks M. Hybertson ,
Bifeng Gao, ,
Swapan K. Bose ,
Joe M. McCorda

The research team are the first to record the continual movement cycle of Nrf2, which sees the protein oscillate in and out of the cell nucleus once every 129 minutes. When stimulated by a health beneficial vegetable-derived substance Nrf2’s cycle sped up to 80 minutes.

Lead researcher Professor Paul Thornalley says, “The way Nrf2 works is very similar to sensors in electronic devices that rely on continual reassessment of their surroundings to provide an appropriate response”.

Discussing the health benefits of the research Professor Thornalley argues:

“The health benefit of Nrf2 oscillating at a fast speed is that surveillance of cell health is increased when most needed, that is, when cells are under threat. By understanding how this process works and increasing Nrf2’s speed without putting cells under threat, new strategies for design of healthier foods and improved drugs can be devised. Current designs may have selected substances with suboptimal if not poor health benefits in some cases.”

Nrf2, a guardian of healthspan and gatekeeper of species longevity
Although aging is a ubiquitous process that prevails in all organisms, the mechanisms governing both the rate of decline in functionality and the age of onset remain elusive. A profound constitutively upregulated cytoprotective response is commonly observed in naturally long-lived species and experimental models of extensions to lifespan (e.g., genetically-altered and/or experimentally manipulated organisms), as indicated by enhanced resistance to stress and upregulated downstream components of the cytoprotective nuclear factor erythroid 2-related factor 2 (Nrf2)-signaling pathway. The transcription factor Nrf2 is constitutively expressed in all tissues, although levels may vary among organs, with the key detoxification organs (kidney and liver) exhibiting highest levels. Nrf2 may be further induced by cellular stressors including endogenous reactive-oxygen species or exogenous electrophiles. The Nrf2-signaling pathway mediates multiple avenues of cytoprotection by activating the transcription of more than 200 genes that are crucial in the metabolism of drugs and toxins, protection against oxidative stress and inflammation, as well as playing an integral role in stability of proteins and in the removal of damaged proteins via proteasomal degradation or autophagy. Nrf2 interacts with other important cell regulators such as tumor suppressor protein 53 (p53) and nuclear factor-kappa beta (NF-κB) and through their combined interactions is the guardian of healthspan, protecting against many age-related diseases including cancer and neurodegeneration. We hypothesize that this signaling pathway plays a critical role in the determination of species longevity and that this pathway may indeed be the master regulator of the aging process.

Commenting on the research, Professor Andreu Palou, coordinator of the EU-funded BIOCLAIMS research programme said “A main nutritional challenge in Europe is to substantiate the beneficial effects of foods that are advertised to the consumers. The approach of the group of Prof Thornalley is opening a fascinating new window.”

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11 September 2014

Notes for Editors:

For a copy of the paper or to speak with Professor Thornalley please email Tom Frew; .(JavaScript must be enabled to view this email address)

The research was funded by the Biotechnology and Biosciences Research Council UK (BBSRC) Diet and Health Research Industry Club (DRINC) and the EU Framework Programme-7 BIOmarkers of Robustness of Metabolic Homeostasis for Nutrigenomics-derived Health CLAIMS Made on Food (BIOCLAIMS) project.

The research was performed by collaboration between the Medical School, Life Sciences and Systems Biology Centre at the University of Warwick: Drs Mingzhan Xue, Hiroshi Momiji, Naila Rabbani, Guy Barker, Till Bretschneider and Tony Shmygol, and Profs David Rand and Paul Thornalley.

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Tom Frew.(JavaScript must be enabled to view this email address)
44-024-767-75910
University of Warwick
@warwickuni